The Program Director (who is also the Project Leader [PL] of Project I) has previously developed the carrageenan microbicide, CarraguardTM (PC-515). Carrageenan belongs to the sulfated polysaccharide class of compounds, many of which are known to have anti-viral properties. Carrageenan, which has a long history of safety, is both the active ingredient and the vehicle in CalTaguard that is currently in FDA approved safety trials involving 400 women with product use for one year. In an effort to increase the efficacy of carrageenan against HIV, the Program Director has developed two modified carrageenan formulations that have shown improved activity against HIV in vitro and against herpes simplex virus-2 (HSV -2) in mice. One modification involves binding zinc to carrageenan and the other is the addition of the sulfated polysaccharide and dispersing agent, lignosulfonic acid (LSA). This Program Project is directed toward investigating the potential of Zn-carrageenan and/or LSA-carrageenan as topical microbicide(s). The Program Director proposes to assay the activity of the two formulations in blocking different strains and clades of HIV in vitro by utilizing a PBMC assay, as well as an assay that he previously developed which employs epithelial cells derived from the human cervix. The formulations will also be evaluated in mice for their effectiveness in preventing vaginal and rectal infection by HSV -2, their ability to block the transport of HIV, and the trafficking of mononuclear blood cells from the vaginal vault. The PLs of other projects in this Program propose the following: Dr. Howett will assay the formulations for efficacy in blocking HIV infection of human vaginal xenografts in a mouse system. Dr. Pope will evaluate how formulations influence dendritic cell function in mediating transmission of HIV, as well as assaying for efficacy in preventing vaginal transmission of SIV in rhesus macaques. Dr. Anazodo will examine the stability, toxicity and pharmacokinetics of Zn-, and LSA-carrageenan. Lastly, Dr. Katz will examine the spreading and retention properties of the formulations in vitro and in humans. Additionally, formulations will be evaluated (in the assays mentioned above) for retaining activity during storage. At the conclusion of the first two years, the findings of all PLs Investigators will be used for the optimization of an evaluation for a final formulation(s). The applicant believes that the proposed research will result in the pre-clinical development of a safe, novel microbicide that is superior in efficacy against HIV.